a) Transcatheter Aortic Valve Implantation (TA VI)
In addition to the initial commercially approved devices for transcatheter aortic valve implantation (TAVI) such as the Edwards-Sapien™ THV balloon expandable bovine bioprosthesis (Edwards Lifesciences INC, Irvine, Calif., USA) and the Core Valve ReValving® System (Medtronic Inc., Minneapolis, Minn., USA), nitinol porcine self-expanding bioprosthesis, a number of newer devices have also recently been CE marked for use via the transapical route. These are the Symetis Acurate (Symetis, Lausanne, Switzerland) and the Jena Valve (JenaValve, Munich, Germany) that are described below in the text.
Several valves for TAVI are currently at an early stage of pre-clinical or clinical evaluation. Referring to Table 1, in general, new valves incorporate features aiming to reduce delivery catheter diameter, facilitate accurate positioning, reduce para-valvular leaks, or allow device retrieval. In the following paragraphs we will describe some of the publicly known programs.
The Direct Flow Medical Aortic Valve, developed by Direct Flow Medical Inc., USA and shown by D in FIG. 1, is a stent-less, non-metallic, expandable device that consists of bovine pericardial leaflets sewed to a Dacron fabric cuff, with an inflatable ring on the aortic side and another on the ventricular side, designed for trans-femoral delivery. Once the valve is positioned, the rings are inflated with saline and contrast until the position and function of the valve has been confirmed. The diluted contrast is then exchanged for an active polymeric medium that, following polymerization, hardens and forms the final support structure.
The Lotus Valve System developed by Boston Scientific Inc., USA, as shown by FIG. 1, is a bioprosthesis consisting of three bovine pericardial leaflets suspended in a self-expanding and self-centering braided nitinol stent frame. It has an active shortening-locking mechanism and an external polyurethane sealing membrane to prevent para-valvular leaks. In the delivery catheter the stent it is in its longitudinal form, with low radial force and small profile. Once the valve has been positioned and the outer catheter is retracted, the prosthesis expands radially, gaining radial force and losing height, effectively locking the valve in place. The valve is designed for trans-femoral delivery.
The Heart Leaflet Technologies (“HLT”) valve, developed by Heart Leaflet Technologies Inc., USA, and as shown by A in FIG. 1, is a porcine pericardial trileaflet valve mounted in a self-inverting nitinol cuff, with 3 nitinol support hoops and with an antireflux collar, designed for trans-femoral delivery.
The JenaClip, developed by Jena Valve Technology GmbH, Munich, Germany and shown by C in FIG. 1, is a bioprosthetic pericardial tissue valve mounted in a self-expanding nitinol stent, as known as the JenaClip, that is built up of 2 layers of “paper clip-like” structures (3 in each layer) that are compressed in a dedicated delivery catheter. It has been designed anatomically to fit in the sinuses of Valsalva with a clip-based anchoring system 20. It is designed for both trans-femoral and trans-apical delivery and recently had CE mark for the transapical route.
The Engager valve, formerly developed by Ventor, recently acquired by Medtronic, Minneapolis, Minn., and shown by H in FIG. 1, is a self-expandable pericardial-tissue prosthesis with a composite nitinol proprietary frame. The outer frame has a crown-shape, with troughs that flare out to anchor the valve in the sinuses. An inner frame has an hourglass shape and is designed to minimize pressure loss at inlet and maximize pressure recovery at outlet, and thereby optimizing fluid dynamics (based on the Venturi effect). This device is specifically dedicated for trans-apical delivery, but more recently a trans-femoral version has been developed.
The AorTx Device, developed by Hansen Medical Inc., Mountain View, Calif. and shown by F in FIG. 1, is a suture-less prosthesis that consists of a pericardial-tissue valve attached to a self-expanding, solid nitinol frame. This frame is folded before deployment. It is repositionable and retrievable. This valve has been designed for both trans-apical and femoral approach through an 18 F delivery system. The ATS 3f Series, developed by ATS Medical, Minneapolis, Minn. and shown by E in FIG. 1, is a self-expandable bioprosthesis mounted in a tubular nitinol frame designed for surgical (ATS 3f Enable) and percutaneous (ATS 3f Entrata) deployments. Six sizes are available, from 19 to 29 mm. The Perceval-Percutaneous, developed by the Sorin Group, Milan, Italy and shown by G in FIG. 1 is a self-expandable bovine pericardial valve with a nitinol panel frame matching the anatomy of the aortic root and sinuses of Valsalva. It has a double sheath that provides enhanced sealing and non-expandable support rods.
The Bailey-Palmaz Perc Valve, developed by Advanced Bio Prosthesis Surfaces, Ltd. San Antonio, Tex. (not shown) is a completely mechanical valve consisting of a monolithic structure of nanosythesized nitinol in a self-expanding cage and nitinol leaflets that also has a nitinol membrane at the base of the valve to reduce paravalvular regurgitation. This new nanosynthetic material has improved stress and fracture resistance and has allowed for a device with a smaller profile, which can be delivered through a 10 F sheath. It is designed to be repositionable and retrievable, and to be delivered by retrograde, antegrade, or transapical approach.
The Paniagua Heart Valve, developed by Endoluminal Technology Research, Miami, Fla. and shown by H in FIG. 1, is a biologic valve having a collapsed profile of 2 mm that must be manually crimped on to a delivery balloon, but that also exists as a self-expanding model. It can be inserted through a 10 F to 18 F sheath, depending on the mounting frame and the final valve diameter. This valve was designed to be used in any heart valve position.
Symetis Acurate valve (Symetis, Lausanne, Switzerland) is a self-expanding nitinol stent has also recently been CE marked for use via the transapical route. The valve is porcine with the stent allowing anchorage via an upper and lower crown along with 3 stabilization arches in a subcoronary position, believed to be the ‘anatomically correct’ position. It is available in 3 sizes: 23 mm, 25 mm and 27 mm, with the ability to be planted sheathless (28 Fr equivalent). The transfemoral version is currently undergoing pre-clinical studies.
Although these valves may incorporate desirable features, little information is currently available on their efficacy, procedural outcomes, and durability.
b) Percutaneous Transcatheter Mitral Valve Repair (“MVR”)
Recently, new techniques have been developed to treat mitral regurgitation (“MR”) with percutaneous approach, in order to restore valve function without surgical incision and cardio-pulmonary by-pass.
Recently a new classification of percutaneous MVR technologies on the basis of functional anatomy grouping the devices into those targeting the leaflets (percutaneous leaflet plication, percutaneous leaflet coaptation, percutaneous leaflet ablation), the annulus (indirect: coronary sinus approach or an asymmetrical approach; direct: true percutaneous or a hybrid approach), the chordae (percutaneous chordal implantation), or the LV (percutaneous LV remodeling) has been proposed, as shown in Table 2.
1. Devices Targeting the Leaflets:
a) Leaflet Plication.
This technology is based on the surgical Alfieri technique which brings the anterior and posterior leaflets together with a suture, creating a “double orifice” MV. This re-establishes leaflet coaptation, thereby reducing MR.
As example, the MitraClip system, developed by Abbott Vascular, Santa Clara, Calif., uses a steerable catheter to deliver a clip to the anterior leaflet and posterior leaflet via trans-septal access. The EVEREST I, developed by Endovascular Valve Edge-to-Edge REpair Study, which was a safety and feasibility study assessing this device has been recently published. Data from the EVEREST II study, randomizing Mitra-Clip versus surgical repair, were recently presented. The device is currently CE marked and used in clinical practice in Europe.
Also, the MitraFlex, developed by TransCardiac Therapeutics, Atlanta, Ga., which deploys a clip to the leaflets via the transapical route, is undergoing pre-clinical testing (this device also allows an artificial chord to be implanted during the same procedure).
b) Leaflet Ablation.
Radiofrequency energy is delivered to the leaflet(s) to effect structural (fibrosis) or functional (reduced motion) alteration.
As example, the Thermocool irrigation ablation electrode, developed by BiosenseWebster, Inc., Diamond Bar, Calif., is a radiofrequency ablation catheter delivered through femoral approach retrogradely into the LV. The catheter is placed in contact with the anterior leaflet, and radiofrequency is delivered, causing scarring and fibrosis and reduced leaflet motion. Proof of concept was demonstrated in an animal study.
c) Leaflet Space Occupier.
The device acting is positioned across the MV orifice to provide a surface against which the leaflets can coapt, reducing MR.
As example, the Percu-Pro device, developed by Cardiosolutions, Stoughton, Mass., consists of a polyurethane-silicone polymer space-occupying buoy that is anchored at the apex through the MV acting as a “spacer” in the mitral orifice. A trans-septal approach is required to implant the anchor in the apex. A phase 1 trial is ongoing.
2. Devices Targeting the Annulus:
a) Indirect Annuloplasty
This approach mimics surgical annuloplasty rings, which are commonly used for repair of both degenerative and functional MR.
Coronary Sinus (“CS”) Approach: This approach involves implantation of devices within the CS with the aim of “pushing” the posterior annulus anteriorly, thereby reducing the septal-lateral (anterior-posterior) dimension of the MA.
As example, the Monarc (previously Viking) system developed by Edwards Lifesciences consists of an outer guide catheter, a smaller delivery catheter, and a nitinol implant. The implant has 3 sections: distal and proximal self-expanding anchors, and a springlike CS and distal great cardiac vein closer, indirectly displacing the posterior annulus anteriorly. The phase 1 trial (Evolution) has been completed. Evolution II study is ongoing.
As another example, the Carillon Mitral Contour System, developed by Cardiac Dimension, Inc., Kirkland, Wash., consists of self-expandable nitinol distal and proximal anchors connected by a nitinol bridge that are placed in the great cardiac vein and proximal CS via a catheter-based system. Tension applied on the system results in cinching of the posterior periannular tissue and deflection of the posterior MA anteriorly. A feasibility study showed modestly reduced septal-lateral dimension and MR. The AMADEUS trial (CARILLON Mitral Annuloplasty Device European Union Study) using the modified CARILLON XE device (Cardiac Dimension, Inc.) has been conducted.
As a further example, the Viacor percutaneous transvenous mitral annuloplasty device, developed by Viacor, Inc., Wilmington, Mass., uses nitinol rods of varying length and stiffness, delivered via a catheter to the CS.
Asymmetrical Approach: This group of devices uses the proximity of the CS to the annulus to try to reshape the mitral annulus (“MA”) but in addition exert traction force on another portion of the left atrium (“LA”) or right atrium, resulting in asymmetrical forces. The aim is to reduce septal-lateral dimension and decrease MR.
As an example, St. Jude Medical, based in Minneapolis, Minn., implanted in animal models comprising 4 helical anchors, 2 loading spacers, a tether rope, and a locking mechanism. The distal pair of anchors is delivered via the CS into the LV myocardium near the posterior leaflet scallop. The proximal pair is implanted via the right atrium into the postero-medial trigone. The 2 pairs of anchors are connected by a cable to effect cinching of the postero-medial MA. Dynamic shortening can be performed manually and reversibly, and the docking mechanism is a self-retracting, nitinol structure that maintains cinched load.
Also, the National Institutes of Health cerclage technology directs a guidewire via the CS into the first septal perforator of the great cardiac vein and, under imaging, across the myocardium to re-enter a right heart chamber. It is ensnared and exchanged for a suture and tension-fixation device.
b) Annuloplasty (Direct):
Percutaneous Mechanical Cinching Approach: This technology reshapes the MA directly without using the CS, approaching the MA from the LV or the LA side. Sutures or some other device are implanted onto the MA itself and used to directly “cinch” the MA. Devices.
As an example, the Mitralign device, developed by Mitralign, Tewksbury, Mass., gains access to the annulus from the transventricular approach. Anchors are placed directly on the posterior MA and connected with a suture, creating a “purse-string” to cinch the MA.
As another example, the Accucinch Annuloplasty System, developed by Guided Delivery Systems, Santa Clara, Calif., uses a transventricular approach. The posterior annulus is cinched circumferentially from trigone to trigone
As a further example, the Millipede system, developed by Millipede, LLC, Ann Arbor, Mich., involves placement of a novel repositionable and retrievable annular ring with a unique attachment system via percutaneous (transseptal) or minimally invasive methods.
Percutaneous Energy-Mediated Cinching Approach: Heat energy is applied to the MA, causing scarring and shrinkage of the MA.
As an example, QuantumCor, developed by QuantumCor, Lake Forest, Calif., effects direct annuloplasty by use of radiofrequency energy to cause scarring and constriction of the MA. It has a loop tip that contains electrodes and thermocouples to regulate the amount of energy delivered.
Also, ReCor device, developed by ReCor, Paris, France, delivers high intensity focused ultrasound circumferentially and perpendicularly to the catheter shaft to induce tissue heating and collagen (and thus MA) shrinkage.
Hybrid Approach: An annuloplasty ring is implanted surgically and can be subsequently adjusted via transseptal access if MR recurs or worsens.
As an example, the Adjustable Annuloplasty Ring, developed by MitralSolutions, Fort Lauderdale, Fla., is implanted surgically and can be adjusted with a mechanical rotating cable.
Also, Dynamic annuloplasty Ring System, developed by MiCardia, Inc., Irving, Calif., is adjusted with radiofrequency energy.
3. Devices Targeting the Chordae:
Synthetic chords or sutures are implanted either from a transapical or transseptal approach and anchored onto the LV myocardium at one end, with the leaflet at the other. The length of the chord is then adjusted to achieve optimal leaflet coaptation, as exemplified by the following devices, the MitraFlex, developed by TransCardiac Therapeutics, and the NeoChord, developed by Neochord, Inc., Minnetonka, Minn.
The MitraFlex and Neochord devices place an anchor in the inner LV myocardium and another on the leaflet via a transapical approach and connect both with a synthetic “chord” trough trans-apical approach.
Babic is based on continuous suture tracks created from the LV puncture through the puncture of the target leaflet and are exteriorized via the trans-septal route. A pledget is apposed onto the exteriorized venous sutures and anchored onto the atrial side of the leaflet by retracting the guiding sutures from the epicardial end. A polymer tube is then interposed between the leaflet and free myocardial wall and secured at the epicardial surface by an adjustable knob.
4. Devices Targeting LV
A device is used to reduce the anterior-posterior dimension of the LV. This indirectly decreases the septallateral annular distance and also brings the LV papillary muscles closer to the leaflets.
The Mardil-BACE, developed by Mardil, Inc., Morrisville, N.C., is a silicone band that is placed around the atrioventricular groove with built-in inflatable chambre placed on the MA. This reshapes the MA for better leaflet coaptation and can be remotely adjusted after implantation. It requires a mini-thoracotomy but is implanted on a beating heart. FIM is ongoing.
5. Percutaneous MVR Technologies
At present time, different devices, such as CardiaAQ, Endovalve, Lutter, Tiara for transcatheter mitral valve replacement therapy using antegrade, transvenous, trans-septal, catheter-based approach are under development. To our knowledge, they are all in the early stages of design and development and have not been approved for clinical use, and in some of them animal studies are ongoing. The challenges are formidable: the MA has an asymmetrical saddle shape, and different anchoring designs might be necessary for different MR etiologies. LV out flow obstruction might occur due to retained native valve tissue. Furthermore paravalvular leaks might also pose a problem.
In all these devices different concepts of anchoring system 20 have been developed to achieve a stabilization of the valve: anchoring below the annulus through hooks (CardiaAQ), subvalvular fixation toward mitral chord or with anchoring in the annulus with movable leaflets (Endovalve) in a nitinol self expanding tubular frame.
As an example, the CardiAQ, developed by CardiAQ Valve Technologies, Inc., Winchester, Mass., prosthesis (Figure B) is delivered transseptally and locks into the inferior and superior surfaces of the mitral annulus. Animal models have been successful.
Also, the Endovalve-Herrmann prosthesis, developed by Endovalve Inc., Princeton, N.J., is implanted from the LA side via a right mini-thoracotomy on a beating heart, as shown in FIG. 3. The device is a foldable nitinol structure that attaches to the native valve with specially designed grippers, is fully valve sparing, and repositionable before release. Animal models have been successful, and a true percutaneous version is planned.
TABLE 2Percutaneous Mitral Valve Regurgitation TechnologiesMechanismSite of Actionof ActionDevicesStatusLeafletsLeaflet Plication1. MitraClipRCTEdge to EdgeCurrently CE mark2. MitraflexPreclinicalLeaflet AblationThermocoolPreclinicalLeaflet Space OccupierPercu-ProPhase 1 trailAnnulusIndirect AnnuloplastyCoronary sinus1. MonarcFIMapproach2. CarillonFeasibility study(CS reshaping)3. ViacorOngoing/completedAsymetrical1. St Jude DevicePreclinicalApproach2. NIH-CerclagetechnologyDirect annuloplastyPercutaneous1. MitralignFIMmechanical2. Accucinch GDSFIMcinching3. Millipede ringPreclinicalsystemPercutaneous energy1. QuantumCorPreclinicalmediated2. ReCorFaesibility studycinchingongoingHybrid1. Mitral solutionsPreclinical2. MiCardiaChordal implantsArtificial chord1. Neochord,PreclinicalTransapical2. MitraFlexArtificial chordBabicPreclinicalTransapical/TranseptalLVLV (and MA)Mardil-BACEFIMremodelingPercutaneousTranseptalCardiaQ prosthesisPreclinicalMVRMinithoracotomyEndovalve-HerrmannPreclinicalTechnologiesprosthesisTransapicalLutter prosthesisPreclinicalTransapicalTiara prosthesisPreclinical
The Lutter prosthesis, a nitinol stent-valve, implanted transapically. It comprised of a left ventricular tubular stent with star shaped left atrial anchoring springs and a trileaflet bovine pericardial valve.
The Tiara (Neovasc, Richmond, BC, Canada) prosthesis, is a nitinol stent valve, implantable transapically. Animal models have been successful, and a true percutaneous version is planned.
As described above, the mitral valve apparatus has multiple components and displays a complex anatomical shape and structure thus limiting the number of any prevailing mitral valve repair solutions. The mitral valve technologies currently under development are actually composed of rigid valve structures, which usually distort the mitral valve plane and apparatus with unknown clinical results. Thus, there is a need for improved designs, which are conforming better to the mitral valve geometry as to keep a physiologic mitral inflow plane following valve apparatus implantation.
In regards to the percutaneous valves under development, several issues need to be considered. Balloon expandable structures depend on permanent plastic deformation induced by device expansion to a specific diameter and length. Although commonly used for treating calcified aortic stenosis, these structures are not proper fit for non-symmetrical shapes such as the mitral valve. Often resulting in para-valvular leaks following device implantation, symmetrical balloon geometries are not ideal. Although, self-expanding structures are an improvement over balloon expandable ones, a one-piece structure in a symmetrical upper and lower part of mitral valve apparatus is not ideal either. Different radial pressures might be needed against surrounding tissue potentially causing deleterious effects such as conduction system disturbances or tissue disruption. The self-positioning singular or multi-disk concept may improve upon the aforementioned limitations by securing the leaflet in between disks of different radial force, aligning a prosthetic valve to blood inflow angle and avoiding dislodgment through anchoring at the base of the mitral valve apparatus.